The focus of this program project is the identification and testing of vaccines for the prevention and treatment of Trypanosoma cruzi infection and Chagas' disease. The protozoan parasite T. cruzi is estimated to infect 16-18 million people and an additional 90 million more at risk of infection. The ultimate consequence of this infection in many individuals, Chagas' disease, is thought to be the single most common cause of congestive heart failure and sudden death in the world and the leading cause of death among young adults in endemic areas of Latin America. Although vector control efforts are making a major impact on the number of new infections in "southern cone" countries, such efforts do little for the 20 million people already infected. In addition, there is considerable concern about whether vector control alone is a long-term solution to the prevention of T. cruzi infection and Chagas' disease. Vaccines are by far the cheapest and easiest way to reduce morbidity and mortality from most infectious diseases and make considerable sense in an infection such as T. cruzi where the infection is rarely detected in the acute stages and therefore is unlikely to be treated before clinical damage occurs. In this proposal, we describe a genome-based approach using both rational and unbiased techniques for vaccine discovery in T. CRUZI. This approach capitalizes on our understanding of immunity and disease inT. cruzi infection, making use of the strength of the mouse model of T. cruzi infection, the information emerging from genome projects with trypanosomitids, and new technical developments for genome analysis and vaccine delivery. Two specific new approaches will be used in this project for the identification of vaccine candidates in T. cruzi: expression library immunization (ELI) and scanning of DNA microarrays. From this combination of approaches, we expect to identify a minimum of 50 strong vaccine candidates for T. cruzi which will then be testing singly and in combination under various conditions in murine models for protection of mice from both lethal infection and from development of severe disease. We will then firm that such molecules are recognized by humans infected with T. cruzi. The ultimate goal of this project is the identification of a vaccine cocktail that can then be tested in additional models and ultimately, in humans.